Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Abstract

The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

An Appraisal on the Value of Using Nutraceutical Based Senolytics and Senostatics in Aging

“…Synthetic compounds with senolytic or senostatic properties can be effective, however, they are not specific, and systemic side effects can be severe and deleterious to healthy cells (Malavolta et al, 2018). Hence, a movement toward the research of natural based compounds (nutraceuticals) with potential antisenescence properties has begun.…”

Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence

“…This effect was attributed to the higher antioxidant activity of T3 compared to tocopherols [ 1 ]. Importantly, T3 are recognized among those compounds that are able to activate the nuclear factor erythroid-2-related factor 2 (Nrf2) [ 38 ], which modulates the transcription of a multitude of cytoprotective genes and is argued to be a lifespan and healthspan extending factor.…”

“…Various antioxidant-independent mechanisms have been proposed to explain the anticancer effect of T3, and, among these, the main are represented by induction of apoptosis, inhibition of cancer cells proliferation, inhibition of angiogenesis, and induction of cellular senescence [ 38 , 50 , 86 ]. In various work focused on the anticancer effect of α-, γ-, and δ-T3 “in vitro”, it has been found that the anticancer action of T3 was related to the induction of mitochondrial dysfunction and apoptosis as well as to the expression of cellular senescence markers [ 61 , 85 ].…”

Is cellular senescence involved in cystic fibrosis?

“…It has been well established that the senescence response observed in this pioneering study was a consequence of the progressive shortening of telomeres [ 2 ]. However, these findings are only the tip of the iceberg in terms of a complex biological response that (in addition to telomere shortening) can be triggered by a multitude of cell-intrinsic and cell-extrinsic stresses, including DNA damage, epigenetic changes, oxidative stress, chronic mitogenic signalling, oncogene activation and inactivation, and the loss of tumour suppressors [ 3 ]. Currently, cellular senescence is understood to be a state of irreversible cell cycle arrest in which cells undergo distinctive phenotypic alterations, including profound chromatin and secretome changes, and tumour suppressor pathway activation [ 4 ].…”